Cargando…
Linearolactone Induces Necrotic-like Death in Giardia intestinalis Trophozoites: Prediction of a Likely Target
Linearolactone (LL) is a neo-clerodane type diterpene that has been shown to exert giardicidal effects; however, its mechanism of action is unknown. This work analyzes the cytotoxic effect of LL on Giardia intestinalis trophozoites and identifies proteins that could be targeted by this active natura...
Autores principales: | , , , , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2022
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9324340/ https://www.ncbi.nlm.nih.gov/pubmed/35890108 http://dx.doi.org/10.3390/ph15070809 |
_version_ | 1784756779843846144 |
---|---|
author | Argüello-García, Raúl Calzada, Fernando Chávez-Munguía, Bibiana Matus-Meza, Audifás-Salvador Bautista, Elihú Barbosa, Elizabeth Velazquez, Claudia Hernández-Caballero, Marta Elena Ordoñez-Razo, Rosa Maria Velázquez-Domínguez, José Antonio |
author_facet | Argüello-García, Raúl Calzada, Fernando Chávez-Munguía, Bibiana Matus-Meza, Audifás-Salvador Bautista, Elihú Barbosa, Elizabeth Velazquez, Claudia Hernández-Caballero, Marta Elena Ordoñez-Razo, Rosa Maria Velázquez-Domínguez, José Antonio |
author_sort | Argüello-García, Raúl |
collection | PubMed |
description | Linearolactone (LL) is a neo-clerodane type diterpene that has been shown to exert giardicidal effects; however, its mechanism of action is unknown. This work analyzes the cytotoxic effect of LL on Giardia intestinalis trophozoites and identifies proteins that could be targeted by this active natural product. Increasing concentrations of LL and albendazole (ABZ) were used as test and reference drugs, respectively. Cell cycle progression, determination of reactive oxygen species (ROS) and apoptosis/necrosis events were evaluated by flow cytometry (FCM). Ultrastructural alterations were analyzed by transmission electron microscopy (TEM). Ligand–protein docking analyses were carried out using the LL structure raised from a drug library and the crystal structure of an aldose reductase homologue (GdAldRed) from G. intestinalis. LL induced partial arrest at the S phase of trophozoite cell cycle without evidence of ROS production. LL induced pronecrotic death in addition to inducing ultrastructural alterations as changes in vacuole abundances, appearance of perinuclear and periplasmic spaces, and deposition of glycogen granules. On the other hand, the in silico study predicted that GdAldRed is a likely target of LL because it showed a favored change in Gibbs free energy for this complex. |
format | Online Article Text |
id | pubmed-9324340 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-93243402022-07-27 Linearolactone Induces Necrotic-like Death in Giardia intestinalis Trophozoites: Prediction of a Likely Target Argüello-García, Raúl Calzada, Fernando Chávez-Munguía, Bibiana Matus-Meza, Audifás-Salvador Bautista, Elihú Barbosa, Elizabeth Velazquez, Claudia Hernández-Caballero, Marta Elena Ordoñez-Razo, Rosa Maria Velázquez-Domínguez, José Antonio Pharmaceuticals (Basel) Article Linearolactone (LL) is a neo-clerodane type diterpene that has been shown to exert giardicidal effects; however, its mechanism of action is unknown. This work analyzes the cytotoxic effect of LL on Giardia intestinalis trophozoites and identifies proteins that could be targeted by this active natural product. Increasing concentrations of LL and albendazole (ABZ) were used as test and reference drugs, respectively. Cell cycle progression, determination of reactive oxygen species (ROS) and apoptosis/necrosis events were evaluated by flow cytometry (FCM). Ultrastructural alterations were analyzed by transmission electron microscopy (TEM). Ligand–protein docking analyses were carried out using the LL structure raised from a drug library and the crystal structure of an aldose reductase homologue (GdAldRed) from G. intestinalis. LL induced partial arrest at the S phase of trophozoite cell cycle without evidence of ROS production. LL induced pronecrotic death in addition to inducing ultrastructural alterations as changes in vacuole abundances, appearance of perinuclear and periplasmic spaces, and deposition of glycogen granules. On the other hand, the in silico study predicted that GdAldRed is a likely target of LL because it showed a favored change in Gibbs free energy for this complex. MDPI 2022-06-29 /pmc/articles/PMC9324340/ /pubmed/35890108 http://dx.doi.org/10.3390/ph15070809 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article Argüello-García, Raúl Calzada, Fernando Chávez-Munguía, Bibiana Matus-Meza, Audifás-Salvador Bautista, Elihú Barbosa, Elizabeth Velazquez, Claudia Hernández-Caballero, Marta Elena Ordoñez-Razo, Rosa Maria Velázquez-Domínguez, José Antonio Linearolactone Induces Necrotic-like Death in Giardia intestinalis Trophozoites: Prediction of a Likely Target |
title | Linearolactone Induces Necrotic-like Death in Giardia intestinalis Trophozoites: Prediction of a Likely Target |
title_full | Linearolactone Induces Necrotic-like Death in Giardia intestinalis Trophozoites: Prediction of a Likely Target |
title_fullStr | Linearolactone Induces Necrotic-like Death in Giardia intestinalis Trophozoites: Prediction of a Likely Target |
title_full_unstemmed | Linearolactone Induces Necrotic-like Death in Giardia intestinalis Trophozoites: Prediction of a Likely Target |
title_short | Linearolactone Induces Necrotic-like Death in Giardia intestinalis Trophozoites: Prediction of a Likely Target |
title_sort | linearolactone induces necrotic-like death in giardia intestinalis trophozoites: prediction of a likely target |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9324340/ https://www.ncbi.nlm.nih.gov/pubmed/35890108 http://dx.doi.org/10.3390/ph15070809 |
work_keys_str_mv | AT arguellogarciaraul linearolactoneinducesnecroticlikedeathingiardiaintestinalistrophozoitespredictionofalikelytarget AT calzadafernando linearolactoneinducesnecroticlikedeathingiardiaintestinalistrophozoitespredictionofalikelytarget AT chavezmunguiabibiana linearolactoneinducesnecroticlikedeathingiardiaintestinalistrophozoitespredictionofalikelytarget AT matusmezaaudifassalvador linearolactoneinducesnecroticlikedeathingiardiaintestinalistrophozoitespredictionofalikelytarget AT bautistaelihu linearolactoneinducesnecroticlikedeathingiardiaintestinalistrophozoitespredictionofalikelytarget AT barbosaelizabeth linearolactoneinducesnecroticlikedeathingiardiaintestinalistrophozoitespredictionofalikelytarget AT velazquezclaudia linearolactoneinducesnecroticlikedeathingiardiaintestinalistrophozoitespredictionofalikelytarget AT hernandezcaballeromartaelena linearolactoneinducesnecroticlikedeathingiardiaintestinalistrophozoitespredictionofalikelytarget AT ordonezrazorosamaria linearolactoneinducesnecroticlikedeathingiardiaintestinalistrophozoitespredictionofalikelytarget AT velazquezdominguezjoseantonio linearolactoneinducesnecroticlikedeathingiardiaintestinalistrophozoitespredictionofalikelytarget |